A novel CB receptor GPR55 and its ligands are involved in regulation of gut movement in rodents.

BACKGROUND: This study was to investigate the effects of the novel cannabinoid receptor - G protein-coupled receptor 55 (GPR55) - and its ligands O-1602 and cannabidiol (CBD) on gastrointestinal (GI) motility in rodents. METHODS: Lipopolysaccharide (LPS) was used in vivo to produce the model of septic ileus. The intestinal motility was measured by recording myoelectrical activity of jejunum in rats, and by measuring GI transit with a charcoal marker in mice, in presence of O-1602 or CBD. Inflammatory response was assessed serologically and histologically. The expression and distribution of GPR55 in the different parts of rat intestine were investigated by real-time PCR and immunohistochemistry. In vitro, the effects of the drugs on the GI movement were investigated by measuring the contraction of the intestinal muscle strips in organ bath, and the intracellular responses of the muscle cells with microelectrode technique. KEY RESULTS: G protein-coupled receptor 55 was expressed in different parts of rat intestine. Lipopolysaccharide significantly inhibited the intestinal motility, increased inflammatory cytokines and GPR55 expression. Pretreatment with CBD normalized LPS-induced hypomotility and improved the inflammatory responses serologically and histologically. Both O-1602 and CBD counteracted LPS-induced disturbances of the gut contraction, but had no effect on the membrane potential of the muscle cells, while cannabinoid type 1 receptor antagonist AM251 and cannabinoid type 2 receptor antagonist AM630 increased the potential. CONCLUSIONS & INFERENCES: G protein-coupled receptor 55 existed throughout the whole intestine of rats. O-1602 or CBD selectively normalized the motility disturbances. Possible mechanisms involved systemic anti-inflammation and the regulation of myoelectrical activity of the intestine.

Cannabinoid type 1 receptor modulates intestinal propulsion by an attenuation of intestinal motor responses within the myenteric part of the peristaltic reflex.

Cannabinoid-1 (CB1) receptor activation affects gastrointestinal propulsion in vivo. It was our aim to further characterize the involved myenteric mechanisms in vivo and in vitro. In CB1(-/-) mice and wild-type littermates we performed in vivo transit experiments by charcoal feeding and in vitro electrophysiological recordings in mouse small intestinal smooth muscle. Ascending neuronal contraction (ANC) following electrical field stimulation was studied in rat ileum in a partitioned organ bath separating the aboral stimulation site from the oral recording site. The knockout animals displayed an accelerated upper gastrointestinal transit compared to control animals. The CB1 receptor antagonist AM251 stimulated the force of the ANC in a concentration dependent manner when added in the oral chamber. Anandamide significantly inhibited the ANC when added in the oral chamber. Neither AM251 nor anandamide had an influence on the contraction latency. No effects were observed when drugs were added in the aboral chamber, proving a CB1 mediated action on the neuromuscular junction. Resting membrane potentials and neuronal induced inhibitory junction potentials in CB1(-/-) mice were unchanged as compared to wild type. However, the electrophysiological slow waves were more sensitive to blockade of Ca(2+) channels in CB1(-/-) mice. Our data strongly suggest a physiological involvement of the CB-1 receptor in the regulation of small intestinal motility. Therefore, CB1 receptors are a promising target for the treatment of motility disorders.

STW 5 (Iberogast) and its individual herbal components modulate intestinal electrophysiology of mice.

STW 5 (Iberogast), a phytomedicine agent consisting of a fixed combination of nine individual plant extracts, is widely used in the treatment of dyspepsia and motility related disorders. Little if anything is known on the possible influence on electrophysiological properties of intestinal smooth muscle by which STW 5 causes its beneficial effects. The aim of the present study was to investigate whether herbal extracts influence electrophysiological parameters of large and small intestine. For this purpose intracellular recordings of smooth muscle cell (SMC) of the circular muscle layer of different parts of mouse intestine were performed using standard microelectrode techniques. The resting membrane potential (RMP), excitatory and inhibitory neurotransmission in proximal colon, the frequency and the amplitude of slow waves in small intestine were investigated. The RMP of SMC was -46.4+/-3.8 mV, n=11 in the colon and -59+/-1.3 mV, n=15 in small intestine. STW 5 significantly depolarized the RMP of colonic (16.6+/-2.2 mV, n=6, p<0.05) and jejunal (9.6+/-1.6 mV, n=7, p<0.05) SMC. This depolarizing effect can be mainly attributed to the constituents of chamomile flower, Angelica root and greater celandine herb. Following the electrical field stimulations (EFSs), junction potentials are influenced in a distinct manner. Excitatory junctions potentials (EJPs) of the colon were not significantly reduced (13.1+/-4.8 vs. 10.1+/-2.8 n.s., n=6) but fast (fIJP) and slow (sIJP) inhibitory junction potentials of the murine colon are reduced significantly by STW 5 (fIJP: 21.6+/-8.1 vs. 11.6+/-2.1 and sIJP: 12.1+/-3.3 vs. 6.1+/-1.3 n=6, p<0.05). The basal frequency of small intestinal slow waves was 39.5+/-1.4 min(-1) and the amplitude was 23.1+/-0.9 mV, n=15. STW 5 significantly reduced amplitude and frequency of the slow waves (11.7+/-0.8 mV; 33.5+/-3.4 min(-1), n=6, p<0.05). This effect on slow waves represents the summation of effects of the nine individual phytoextracts. Whereas Angelica root and chamomile flower completely blocked the slow wave activity, bitter candy tuft increased the frequency and amplitude, greater celandine herb reduced frequency and amplitude of the slow wave, peppermint leaf reduced frequency and left amplitude unchanged and liquorice root, caraway fruit and lemon balm leaf had no effects in basic electrophysiological properties of SMC. This study demonstrates that STW 5 causes changes in SMC RMP, excitatory and inhibitory neurotransmission and slow wave rhythmicity. These effects represent a summation effect of different constituents of this phytotherapeuticum and prove that STW 5 has characteristic effects on intestinal electrophysiology.